BioPAX pathway converted from "HMGB1 binds LPS" in the Reactome database. LEFT-TO-RIGHT HMGB1 binds LPS This event has been computationally inferred from an event that has been demonstrated in another species.<p>The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<p><a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a> hmgb1 HC23,45-HMGB1 Q6P4N5 Reactome DB_ID: 10556162 extracellular region GENE ONTOLOGY GO:0005576 UniProt:Q6P4N5 hmgb1 Xenopus tropicalis NCBI Taxonomy 8364 UniProt Q6P4N5 23 EQUAL L-cystine (cross-link) MOD MOD:00034 2 EQUAL 215 EQUAL Reactome Database ID Release 83 10556162 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10556162 Reactome R-XTR-6797422 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6797422.1 Reactome http://www.reactome.org LPS Gram Negative Bacterial Lipopolysaccharide lipopolysaccharide Reactome DB_ID: 166005 lipopolysaccharide [ChEBI:16412] lipopolysaccharide lipopolysaccharides LPS ChEBI CHEBI:16412 Reactome Database ID Release 83 166005 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=166005 Reactome R-ALL-166005 4 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-166005.4 HC23,45-HMGB1:LPS Reactome DB_ID: 10556168 1 1 Reactome Database ID Release 83 10556168 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10556168 Reactome R-XTR-6801229 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6801229.1 Reactome Database ID Release 83 10556170 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=10556170 Reactome R-XTR-6804100 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-XTR-6804100.1 High mobility group box 1 (HMGB1) is an ubiquitous nuclear protein that is actively secreted by innate immune cells and/or released passively by necrotic or damaged cells in response to infection or injury (Andersson U et al. 2000; Scaffidi P et al. 2002; Bonaldi T et al. 2003; Chen G et al. 2004; Beyer C et al. 2012; Yang H et al. 2013). Outside the cell, HMGB1 can serve as an alarmin to activate innate immune responses including chemotaxis and cytokine release in both normal and aberrant immunity (Andersson U et al. 2000; Zetterström CK et al. 2002; Voll RE et al. 2008; Harris HE et al. 2012; Diener KR et al. 2013; Yang H et al. 2013).<p> HMGB1 can form immunostimulatory complexes with cytokines and other endogenous and exogenous ligands such as bacterial lipopolysaccharide (LPS) to potentiate proinflammatory response (Youn JH et al. 2008, 2011; Wähämaa H et al. 2011; Hreggvidsdottir HS et al. 2009). The activity of HMGB1 depended on the redox state of three cysteines at positions 23, 45 and 106 (C23, C45 and C106) (Urbonaviciute V et al. 2009; Venereau E et al. 2012, 2013; Yang H et al. 2012, 2013). Tandem mass spectrometric analysis revealed that the inflammatory activities of HMGB1 required both the formation of an intramolecular disulfide bond between C23 and C45 and the reduced state of C106 (thiol state, C106-SH) (Yang H et al. 2012; Venereau E et al. 2012). Both terminal oxidation of these cysteines to sulfonates (CySO3–) with reactive oxygen species (ROS) and their complete reduction to thiols (CySH) abrogated the cytokine-stimulating activity of HMGB1 in cultured human primary macrophages and mouse macrophage-like RAW 264.7 cells (Yang H et al. 2012; Venereau E et al. 2012).<p>HMGB1 binding to LPS facilitated transfer of LPS to CD14 and enhanced TNFalpha production in human peripheral blood mononuclear cells (PBMCs) (Youn JH et al. 2008). HMGB1 in complex with LPS boosted proinflammatory cytokine- and matrix metalloproteinase (MMP3) production in synovial fibroblasts obtained from rheumatoid arthritis (RA) and osteoarthritis (OA) patients (Wähämaa H et al. 2011; He ZW et al. 2013).<p> In addition to its ability to act in a synergy with LPS and other ligands, HMGB1 was shown to stimulate cells by direct interaction with innate immune receptors such as TLR4:LY96 (Yang H et al. 2010; Yang H et al. 2015). 22344226 Pubmed 2012 The extracellular release of DNA and HMGB1 from Jurkat T cells during in vitro necrotic cell death Beyer, Christian Stearns, Nancy A Giessl, Adreas Distler, Jörg H W Schett, Georg Pisetsky, David S Innate Immun 18:727-37 19564572 Pubmed 2009 The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation Hreggvidsdottir, Hulda Sigridur Ostberg, Therese Wähämaa, Heidi Schierbeck, Hanna Aveberger, Ann-Charlotte Klevenvall, Lena Palmblad, Karin Ottosson, Lars Andersson, Ulf Harris, Helena Erlandsson J. Leukoc. Biol. 86:655-62 21871094 Pubmed 2011 High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts Wähämaa, Heidi Schierbeck, Hanna Hreggvidsdottir, Hulda S Palmblad, Karin Aveberger, Anne-Charlotte Andersson, Ulf Harris, Helena Erlandsson Arthritis Res. Ther. 13:R136 21660935 Pubmed 2011 Identification of lipopolysaccharide-binding peptide regions within HMGB1 and their effects on subclinical endotoxemia in a mouse model Youn, Ju Ho Kwak, Man Sup Wu, Jie Kim, Eun Sook Ji, Yeounjung Min, Hyun Jin Yoo, Ji-Ho Choi, Ji Eun Cho, Hyun-Soo Shin, Jeon-Soo Eur. J. Immunol. 41:2753-62 14532127 Pubmed 2003 Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion Bonaldi, Tiziana Talamo, Fabio Scaffidi, Paola Ferrera, Denise Porto, Annalisa Bachi, Angela Rubartelli, Anna Agresti, Alessandra Bianchi, Marco E EMBO J. 22:5551-60 25559892 Pubmed 2015 MD-2 is required for disulfide HMGB1-dependent TLR4 signaling Yang, Huan Wang, Haichao Ju, Zhongliang Ragab, Ahmed A Lundbäck, Peter Long, Wei Valdes-Ferrer, Sergio I He, Mingzhu Pribis, John P Li, Jianhua Lu, Ben Gero, Domokos Szabo, Csaba Antoine, Daniel J Harris, Helena E Golenbock, Doug T Meng, Jianmin Roth, Jesse Chavan, Sangeeta S Andersson, Ulf Billiar, Timothy R Tracey, Kevin J Al-Abed, Yousef J. Exp. Med. 212:5-14 15331624 Pubmed 2004 Bacterial endotoxin stimulates macrophages to release HMGB1 partly through CD14- and TNF-dependent mechanisms Chen, Guoqian Li, Jianhua Ochani, Mahendar Rendon-Mitchell, Beatriz Qiang, Xiaoling Susarla, Seenu Ulloa, Luis Yang, Huan Fan, Saijun Goyert, Sanna M Wang, Ping Tracey, Kevin J Sama, Andrew E Wang, Haichao J. Leukoc. Biol. 76:994-1001 18354232 Pubmed 2008 High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes Youn, Ju Ho Oh, Young Joo Kim, Eun Sook Choi, Ji Eun Shin, Jeon-Soo J. Immunol. 180:5067-74 24302816 Pubmed 2013 HMGB1 acts in synergy with lipopolysaccharide in activating rheumatoid synovial fibroblasts via p38 MAPK and NF-κB signaling pathways He, Zheng-Wen Qin, Yang-Hua Wang, Zhi-Wei Chen, Yan Shen, Qian Dai, Sheng-Ming Mediators Inflamm. 2013:596716 19811284 Pubmed 2009 Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis Urbonaviciute, Vilma Meister, Silke Fürnrohr, Barbara G Frey, Benjamin Gückel, Eva Schett, Georg Herrmann, Martin Voll, Reinhard E Autoimmunity 42:305-7 12110890 Pubmed 2002 Release of chromatin protein HMGB1 by necrotic cells triggers inflammation Scaffidi, Paola Misteli, Tom Bianchi, Marco E Nature 418:191-5 23207101 Pubmed 2013 HMGB1 and leukocyte migration during trauma and sterile inflammation Venereau, Emilie Schiraldi, Milena Uguccioni, Mariagrazia Bianchi, Marco E Mol. Immunol. 55:76-82 22869893 Pubmed 2012 Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release Venereau, Emilie Casalgrandi, Maura Schiraldi, Milena Antoine, Daniel J Cattaneo, Angela De Marchis, Francesco Liu, Jaron Antonelli, Antonella Preti, Alessandro Raeli, Lorenzo Shams, Sara Samadi Yang, Huan Varani, Luca Andersson, Ulf Tracey, Kevin J Bachi, Angela Uguccioni, Mariagrazia Bianchi, Marco E J. Exp. Med. 209:1519-28 20547845 Pubmed 2010 A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release Yang, Huan Hreggvidsdottir, Hulda S Palmblad, Karin Wang, Haichao Ochani, Mahendar Li, Jianhua Lu, Ben Chavan, Sangeeta Rosas-Ballina, Mauricio Al-Abed, Yousef Akira, Shizuo Bierhaus, Angelika Erlandsson-Harris, Helena Andersson, Ulf Tracey, Kevin J Proc. Natl. Acad. Sci. U.S.A. 107:11942-7 16878026 Pubmed 2006 HMGB1 signals through toll-like receptor (TLR) 4 and TLR2 Yu, Man Wang, Haichao Ding, Aihao Golenbock, DT Latz, Eicke Czura, Christopher J Fenton, Matthew J Tracey, Kevin J Yang, Huan Shock 26:174-9 10952726 Pubmed 2000 High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes Andersson, U Wang, H Palmblad, K Aveberger, A C Bloom, O Erlandsson-Harris, H Janson, A Kokkola, R Zhang, M Yang, H Tracey, K J J. Exp. Med. 192:565-70 23446148 Pubmed 2013 The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis Yang, Huan Antoine, Daniel J Andersson, Ulf Tracey, Kevin J J. Leukoc. Biol. 93:865-73 22105604 Pubmed 2012 Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1) Yang, Huan Lundbäck, Peter Ottosson, Lars Erlandsson-Harris, Helena Venereau, Emilie Bianchi, Marco E Al-Abed, Yousef Andersson, Ulf Tracey, Kevin J Antoine, Daniel J Mol. Med. 18:250-9 inferred from electronic annotation EVIDENCE CODE ECO:0000203